Murine obscurin and Obsl1 have functionally redundant roles in sarcolemmal integrity, sarcoplasmic reticulum organization, and muscle metabolism.

Biological roles of obscurin and its close homolog Obsl1 (obscurin-like 1) have been enigmatic. While obscurin is highly expressed in striated muscles, Obsl1 is found ubiquitously. Accordingly, obscurin mutations have been linked to myopathies, whereas mutations in Obsl1 result in 3M-growth syndrome. To further study unique and redundant functions of these closely related proteins, we generated and characterized Obsl1 knockouts. Global Obsl1 knockouts are embryonically lethal. In contrast, skeletal muscle-specific Obsl1 knockouts show a benign phenotype similar to obscurin knockouts. Only deletion of both proteins and removal of their functional redundancy revealed their roles for sarcolemmal stability and sarcoplasmic reticulum organization. To gain unbiased insights into changes to the muscle proteome, we analyzed tibialis anterior and soleus muscles by mass spectrometry, uncovering additional changes to the muscle metabolism. Our analyses suggest that all obscurin protein family members play functions for muscle membrane systems

Gauge theories as a geometrical issue of a Kaluza-Klein framework

We present a geometrical unification theory in a Kaluza-Klein approach that achieve the geometrization of a generic gauge theory bosonic component. We show how it is possible to derive the gauge charge conservation from the invariance of the model under extra-dimensional translations and to geometrize gauge connections for spinors, thus we can introduce the matter just by free spinorial fields. Then, we present the applications to i)a pentadimensional manifold $V^{4}\otimes S^{1}$, so reproducing the original Kaluza-Klein theory, unless some extensions related to the rule of the scalar field contained in the metric and the introduction of matter by spinors with a phase dependence from the fifth coordinate, ii)a seven-dimensional manifold $V^{4}\otimes S^{1}\otimes S^{2}$, in which we geometrize the electro-weak model by introducing two spinors for any leptonic family and quark generation and a scalar field with two components with opposite hypercharge, responsible of spontaneous symmetry breaking.Comment: 37 pages, no figure

Perinatal Stress Programs Sex Differences in the Behavioral and Molecular Chronobiological Profile of Rats Maintained Under a 12-h Light-Dark Cycle

Stress and the circadian systems play a major role in an organism’s adaptation to environmental changes. The adaptive value of the stress system is reactive while that of the circadian system is predictive. Dysfunctions in these two systems may account for many clinically relevant disorders. Despite the evidence that interindividual differences in stress sensitivity and in the functioning of the circadian system are related, there is limited integrated research on these topics. Moreover, sex differences in these systems are poorly investigated. We used the perinatal stress (PRS) rat model, a well-characterized model of maladaptive programming of reactive and predictive adaptation, to monitor the running wheel behavior in male and female adult PRS rats, under a normal light/dark cycle as well as in response to a chronobiological stressor (6-h phase advance/shift). We then analyzed across different time points the expression of genes involved in circadian clocks, stress response, signaling, and glucose metabolism regulation in the suprachiasmatic nucleus (SCN). In the unstressed control group, we found a sex-specific profile that was either enhanced or inverted by PRS. Also, PRS disrupted circadian wheel-running behavior by inducing a phase advance in the activity of males and hypoactivity in females and increased vulnerability to chronobiological stress in both sexes. We also observed oscillations of several genes in the SCN of the unstressed group in both sexes. PRS affected males to greater extent than females, with PRS males displaying a pattern similar to unstressed females. Altogether, our findings provide evidence for a specific profile of dysmasculinization induced by PRS at the behavioral and molecular level, thus advocating the necessity to include sex as a biological variable to study the set-up of circadian system in animal models

Nouvelles avancées dans l'hypothèse glutamatergique de la dépression : une étude neurochimique et pharmacologique dans le modèle de stress prénatal chez le rat

Le stress est un facteur de risque majeur pour les troubles de l'humeur comme l'anxiété et la dépression. Les rats exposés à un stress prénatal de contention (PRS) – i.e. la progéniture de mères soumises à des épisodes répétés de stress au cours des 10 derniers jours de gestation - développent des changements biochimiques et comportementaux durables qui résument certains traits de la dépression et de l'anxiété. Un nombre grandissant de travaux suggère l'implication du système glutamatergique hippocampique dans ces troubles. L'hippocampe fait partie intégrante de la programmation altérée déclenchée par le PRS. Nous avons donc décidé d’étudier l'hypothèse glutamatergique de la dépression chez le rat PRS, en mettant l'accent sur les mécanismes de neuroadaptation dans le circuit hippocampique. Nous avons démontré que les rats PRS présentaient une altération de la libération de glutamate dans l'hippocampe ventral, partie spécifique de l’hippocampe reliée au stress et aux émotions. Remarquablement, des injections locales de produits qui améliorent la libération du glutamate dans l’hippocampe ventral (i.e. un cocktail d’antagonistes des récepteurs au GABA-B et mGlu2/3) exerçaient un fort effet anxiolytique chez les rats PRS. De plus, un traitement chronique avec des antidépresseurs conventionnels améliorait la libération du glutamate dans l’hippocampe ventral et corrigeait le phénotype de type anxieux/dépressif induit par le PRS. Sachant que l’hippocampe ventral module la programmation motrice striatale, nous avons étendu notre étude chez le rat PRS à la catalepsie induite par l'halopéridol, qui modélise le parkinsonisme pharmacologique chez l'Homme. Nous avons constaté que les rats PRS étaient résistants à la catalepsie induite par l’halopéridol, comme le résultat d'une activité augmentée des noyaux thalamiques moteurs, et tel que révélé par le compte stéréologique des neurones c-Fos-positifs. Nos résultats renforcent la théorie glutamatergique dans les troubles de l'humeur liés au stress et suggèrent qu'une déficience de l'hippocampe ventral et son influence sur le circuit striatal sont des éléments clé du programme neuroplastique induit par le PRS.Stress is a major risk factor for mood disorders, such as anxiety and depression. Rats exposed to prenatal restraint stress (PRS) - i.e. the offspring of dams submitted to repeated episodes of stress during the last 10 days of gestation - develop long-lasting biochemical and behavioral changes that recapitulate some traits of depression and anxiety. Mounting evidence suggests the involvement of hippocampal glutamatergic system in such disorders. Interestingly, the hippocampus represents an integral part of the altered programming triggered by PRS. Hence, we decided to investigate the glutamatergic hypothesis of depression in the rat model of PRS focusing on mechanisms of neuroadaptation within the hippocampal circuit. We found that PRS rats showed an impairment of glutamate release, in the ventral hippocampus, which is the specific portion of the hippocampus related to stress and emotions. Remarkably, local injections of drugs that enhanced glutamate release in the ventral hippocampus (i.e., a cocktail of GABA-B and mGlu2/3 receptor antagonists) had strong anxiolytic effects in PRS rats. In addition, chronic treatment with conventional antidepressant drugs enhanced glutamate release in the ventral hippocampus and corrected the anxious/depressive-like phenotype induced by PRS. Knowing that the ventral hippocampus modulates striatal motor programming, we extended the study of PRS rats to haloperidol-induced catalepsy, which models pharmacological parkinsonism in humans. We found that PRS rats were resistant to haloperidol-induced catalepsy as a result of an increased activity of motor thalamic nuclei, as assessed by stereologic counting of c-Fos-positive neurons. Our findings support the glutamatergic theory of stress-related mood disorders and suggest that an impairment of the ventral hippocampus and its influence on striatal circuit are key components of the neuroplastic program induced by PRS

Stress Response and Perinatal Reprogramming: Unraveling (Mal)adaptive Strategies

Environmental stressors induce coping strategies in the majority of individuals. The stress response, involving the activation of the hypothalamic-pituitary-adrenocortical axis and the consequent release of corticosteroid hormones, is indeed aimed at promoting metabolic, functional, and behavioral adaptations. However, behavioral stress is also associated with fast and long-lasting neurochemical, structural, and behavioral changes, leading to long-term remodeling of glutamate transmission, and increased susceptibility to neuropsychiatric disorders. Of note, early-life events, both in utero and during the early postnatal life, trigger reprogramming of the stress response, which is often associated with loss of stress resilience and ensuing neurobehavioral (mal)adaptations. Indeed, adverse experiences in early life are known to induce long-term stress-related neuropsychiatric disorders in vulnerable individuals. Here, we discuss recent findings about stress remodeling of excitatory neurotransmission and brain morphology in animal models of behavioral stress. These changes are likely driven by epigenetic factors that lie at the core of the stress-response reprogramming in individuals with a history of perinatal stress. We propose that reprogramming mechanisms may underlie the reorganization of excitatory neurotransmission in the short- and long-term response to stressful stimuli

Nouvelles avancées dans l'hypothèse glutamatergique de la dépression (une étude neurochimique et pharmacologique dans le modèle de stress prénatal chez le rat)

Le stress est un facteur de risque majeur pour les troubles de l'humeur comme l'anxiété et la dépression. Les rats exposés à un stress prénatal de contention (PRS) i.e. la progéniture de mères soumises à des épisodes répétés de stress au cours des 10 derniers jours de gestation - développent des changements biochimiques et comportementaux durables qui résument certains traits de la dépression et de l'anxiété. Un nombre grandissant de travaux suggère l'implication du système glutamatergique hippocampique dans ces troubles. L'hippocampe fait partie intégrante de la programmation altérée déclenchée par le PRS. Nous avons donc décidé d étudier l'hypothèse glutamatergique de la dépression chez le rat PRS, en mettant l'accent sur les mécanismes de neuroadaptation dans le circuit hippocampique. Nous avons démontré que les rats PRS présentaient une altération de la libération de glutamate dans l'hippocampe ventral, partie spécifique de l hippocampe reliée au stress et aux émotions. Remarquablement, des injections locales de produits qui améliorent la libération du glutamate dans l hippocampe ventral (i.e. un cocktail d antagonistes des récepteurs au GABA-B et mGlu2/3) exerçaient un fort effet anxiolytique chez les rats PRS. De plus, un traitement chronique avec des antidépresseurs conventionnels améliorait la libération du glutamate dans l hippocampe ventral et corrigeait le phénotype de type anxieux/dépressif induit par le PRS. Sachant que l hippocampe ventral module la programmation motrice striatale, nous avons étendu notre étude chez le rat PRS à la catalepsie induite par l'halopéridol, qui modélise le parkinsonisme pharmacologique chez l'Homme. Nous avons constaté que les rats PRS étaient résistants à la catalepsie induite par l halopéridol, comme le résultat d'une activité augmentée des noyaux thalamiques moteurs, et tel que révélé par le compte stéréologique des neurones c-Fos-positifs. Nos résultats renforcent la théorie glutamatergique dans les troubles de l'humeur liés au stress et suggèrent qu'une déficience de l'hippocampe ventral et son influence sur le circuit striatal sont des éléments clé du programme neuroplastique induit par le PRS.Stress is a major risk factor for mood disorders, such as anxiety and depression. Rats exposed to prenatal restraint stress (PRS) - i.e. the offspring of dams submitted to repeated episodes of stress during the last 10 days of gestation - develop long-lasting biochemical and behavioral changes that recapitulate some traits of depression and anxiety. Mounting evidence suggests the involvement of hippocampal glutamatergic system in such disorders. Interestingly, the hippocampus represents an integral part of the altered programming triggered by PRS. Hence, we decided to investigate the glutamatergic hypothesis of depression in the rat model of PRS focusing on mechanisms of neuroadaptation within the hippocampal circuit. We found that PRS rats showed an impairment of glutamate release, in the ventral hippocampus, which is the specific portion of the hippocampus related to stress and emotions. Remarkably, local injections of drugs that enhanced glutamate release in the ventral hippocampus (i.e., a cocktail of GABA-B and mGlu2/3 receptor antagonists) had strong anxiolytic effects in PRS rats. In addition, chronic treatment with conventional antidepressant drugs enhanced glutamate release in the ventral hippocampus and corrected the anxious/depressive-like phenotype induced by PRS. Knowing that the ventral hippocampus modulates striatal motor programming, we extended the study of PRS rats to haloperidol-induced catalepsy, which models pharmacological parkinsonism in humans. We found that PRS rats were resistant to haloperidol-induced catalepsy as a result of an increased activity of motor thalamic nuclei, as assessed by stereologic counting of c-Fos-positive neurons. Our findings support the glutamatergic theory of stress-related mood disorders and suggest that an impairment of the ventral hippocampus and its influence on striatal circuit are key components of the neuroplastic program induced by PRS.LILLE1-Bib. Electronique (590099901) / SudocSudocFranceF

Perspective on equitable translational studies and clinical support for an unbiased inclusion of the LGBTQIA2S+community.

Research regarding the mental health of the Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual, 2 Spirit (LGBTQIA2S+) community has been historically biased by individual and structural homophobia, biphobia, and transphobia, resulting in research that does not represent the best quality science. Furthermore, much of this research does not serve the best interests or priorities of LGBTQIA2S + communities, despite significant mental health disparities and great need for quality mental health research and treatments in these populations. Here, we will highlight how bias has resulted in missed opportunities for advancing understanding of mental health within LGBTQIA2S + communities. We cite up-to-date research on mental health disparities facing the LGBTQIA2S + community and targeted treatment strategies, as well as guidance from health care professionals. Importantly, research is discussed from both preclinical and clinical perspectives, providing common language and research priorities from a translational perspective. Given the rising tide of anti-transgender sentiment among certain political factions, we further emphasize and discuss the impact of historical and present day ciscentrism and structural transphobia in transgender mental health research, from both clinical and translational perspectives, with suggestions for future directions to improve the quality of this field. Finally, we address current best practices for treatment of mental health issues in this community. This approach provides an opportunity to dispel myths regarding the LGBTQIA2S + community as well as inform the scientific community of best practices to work with this community in an equitable manner. Thus, our approach ties preclinical and clinical research within the LGBTQIA2S + community

Perinatal Stress Programs Sex Differences in the Behavioral and Molecular Chronobiological Profile of Rats Maintained Under a 12-h Light-Dark Cycle

International audienceStress and the circadian systems play a major role in an organism’s adaptation to environmental changes. The adaptive value of the stress system is reactive while that of the circadian system is predictive. Dysfunctions in these two systems may account for many clinically relevant disorders. Despite the evidence that interindividual differences in stress sensitivity and in the functioning of the circadian system are related, there is limited integrated research on these topics. Moreover, sex differences in these systems are poorly investigated. We used the perinatal stress (PRS) rat model, a well-characterized model of maladaptive programming of reactive and predictive adaptation, to monitor the running wheel behavior in male and female adult PRS rats, under a normal light/dark cycle as well as in response to a chronobiological stressor (6-h phase advance/shift). We then analyzed across different time points the expression of genes involved in circadian clocks, stress response, signaling, and glucose metabolism regulation in the suprachiasmatic nucleus (SCN). In the unstressed control group, we found a sex-specific profile that was either enhanced or inverted by PRS. Also, PRS disrupted circadian wheel-running behavior by inducing a phase advance in the activity of males and hypoactivity in females and increased vulnerability to chronobiological stress in both sexes. We also observed oscillations of several genes in the SCN of the unstressed group in both sexes. PRS affected males to greater extent than females, with PRS males displaying a pattern similar to unstressed females. Altogether, our findings provide evidence for a specific profile of dysmasculinization induced by PRS at the behavioral and molecular level, thus advocating the necessity to include sex as a biological variable to study the set-up of circadian system in animal models

Reduced maternal behavior caused by gestational stress is predictive of life span changes in risk-taking behavior and gene expression due to altering of the stress/anti-stress balance

Exposure of the mother to adverse events during pregnancy is known to induce pathological programming of the HPA axis in the progeny, thereby increasing the vulnerability to neurobehavioral disorders. Maternal care plays a crucial role in the programming of the offspring, and oxytocin plays a key role in mother/pup interaction. Therefore, we investigated whether positive modulation of maternal behavior by activation of the oxytocinergic system could reverse the long-term alterations induced by perinatal stress (PRS; gestational restraint stress 3 times/day during the last ten days of gestation) on HPA axis activity, risk-taking behavior in the elevated-plus maze, hippocampal mGlu5 receptor and gene expression in Sprague-Dawley rats. Stressed and control unstressed dams were treated during the first postpartum week with an oxytocin receptor agonist, carbetocin (1 mg/kg, i.p.). Remarkably, reduction of maternal behavior was predictive of behavioral disturbances in PRS rats as well as of the impairment of the oxytocin and its receptor gene expression. Postpartum carbetocin corrected the reduction of maternal behavior induced by gestational stress as well as the impaired oxytocinergic system in the PRS progeny, which was associated with reduced risk-taking behavior. Moreover, postpartum carbetocin had an anti-stress effect on HPA axis activity in the adult PRS progeny and increased hippocampal mGlu5 receptor expression in aging. In conclusion, the activation of the oxytocinergic system in the early life plays a protective role against the programming effect by adverse experiences and could be considered as a novel and powerful potential therapeutic target for stress-related disorders

Evidence for an imbalance between tau O-GlcNAcylation and phosphorylation in the hippocampus of a mouse model of Alzheimer's disease

Intracellular accumulation of hyperphosphorylated tau protein is linked to neuronal degeneration in Alzheimer's disease (AD). Mounting evidence suggests that tau phosphorylation and O-N-acetylglucosamine glycosylation (O-GlcNAcylation) are mutually exclusive post-translational modifications. O-GlcNAcylation depends on 3-5% of intracellular glucose that enters the hexosamine biosynthetic pathway. To our knowledge, the existence of an imbalance between tau phosphorylation and O-GlcNAcylation has not been reported in animal models of AD, as yet. Here, we used triple transgenic (3xTg-AD) mice at 12 months, an age at which hyperphosphorylated tau is already detected and associated with cognitive decline. In these mice, we showed that tau was hyperphosphorylated on both Ser396 and Thr205 in the hippocampus, and to a lower extent and exclusively on Thr205 in the frontal cortex. Tau O-GlcNAcylation, assessed in tau immunoprecipitates, was substantially reduced in the hippocampus of 3xTg-AD mice, with no changes in the frontal cortex or in the cerebellum. No changes in the expression of the three major enzymes involved in O-GlcNAcylation, i.e., glutamine fructose-6-phosphate amidotransferase, O-linked β-N-acetylglucosamine transferase, and O-GlcNAc hydrolase were found in the hippocampus of 3xTg-AD mice. These data demonstrate that an imbalance between tau phosphorylation and O-GlcNAcylation exists in AD mice, and strengthens the hypothesis that O-GlcNAcylation might be targeted by disease modifying drugs in AD